Repellent guidance of regenerating optic axons by chondroitin sulfate glycosaminoglycans in zebrafish

We analyzed the role of chondroitin sulfate (CS) glycosaminoglycans, putative inhibitors of axonal regeneration in mammals, in the regenerating visual pathway of adult zebrafish. In the adult, CS immunoreactivity was not detectable before or after an optic nerve crush in the optic nerve and tract but was constitutively present in developing and adult nonretinorecipient pretectal brain nuclei, where CSs may form a boundary preventing regenerating optic fibers from growing into these inappropriate locations. Enzymatic removal of CSs by chondroitinase ABC after optic nerve crush significantly increased the number of animals showing erroneous growth of optic axons into the nonretinorecipient magnocellular superficial/ posterior pretectal nucleus (83 % vs 42 % in controls). In vitro, a substrate border of CSs, but not heparan sulfates, strongly repelled regenerating retinal axons from adult zebrafish. We conclude that CSs contribute to repellent axon guidance during regeneration of the optic projection in zebrafish. Key words: CNS regeneration; extracellular matrix; chondroitin sulfate proteoglycans; heparan sulfate; chondroitinase ABC; tenascin-R; retinal ganglion cell axons; neurite outgrowth Fish and amphibians, in contrast to mammals, are capable of regenerating lesioned axon tracts in the adult CNS (for review, see Martin et al., 1994; Bernhardt, 1999). Regenerative failure of mammalian CNS axons is, at least in part, attributed to inhibitory molecules that are expressed by glial cells (for review, see Fawcett and Geller, 1998; Qiu et al., 2000). Expression of chondroitin sulfate (CS)-carrying proteoglycans (CSPGs) is increased in a CNS lesion site, where these molecules may form a barrier to regrowing axons (for review, see Fawcett and Asher, 1999; Bovolenta and Fernaud-Espinosa, 2000). CSs contribute to this inhibition, because treatment of lesion sites with chondroitinase renders these more supportive to axon growth in vitro (McKeo

PlexinA3 restricts spinal exit points and branching of trunk motor nerves in embryonic zebrafish

The pioneering primary motor axons in the zebrafish trunk are guided by multiple cues along their pathways. Plexins are receptor components for semaphorins that influence motor axon growth and path finding. We cloned plexinA3 in zebrafish and localized plexinA3 mRNA in primary motor neurons during axon outgrowth. Antisense morpholino knock-down led to substantial errors in motor axon growth. Errors comprised aberrant branching of primary motor nerves as well as additional exit points of axons from the spinal cord. Excessively branched and supernumerary nerves were found in both ventral and dorsal pathways of motor axons. The trunk environment and several other types of axons, including trigeminal axons, were not detectably affected by plexinA3 knock-down. RNA overexpression rescued all morpholino effects. Synergistic effects of combined morpholino injections indicate interactions of plexinA3 with semaphorin3A homologs. Thus, plexinA3 is a crucial receptor for axon guidance cues in primary motor neurons

A synthetic cell permeable antioxidant protects neurons against acute oxidative stress

Funding: Royal Society University Fellowship and grant (RF 120645) (JEL).Excessive reactive oxygen species (ROS) can damage proteins, lipids, and DNA, which result in cell damage and death. The outcomes can be acute, as seen in stroke, or more chronic as observed in age-related diseases such as Parkinson’s disease. Here we investigate the antioxidant ability of a novel synthetic flavonoid, Proxison (7-decyl-3-hydroxy-2-(3,4,5-trihydroxyphenyl)-4-chromenone), using a range of in vitro and in vivo approaches. We show that, while it has radical scavenging ability on par with other flavonoids in a cell-free system, Proxison is orders of magnitude more potent than natural flavonoids at protecting neural cells against oxidative stress and is capable of rescuing damaged cells. The unique combination of a lipophilic hydrocarbon tail with a modified polyphenolic head group promotes efficient cellular uptake and moderate mitochondrial enrichment of Proxison. Importantly, in vivo administration of Proxison demonstrated effective and well tolerated neuroprotection against cell loss in a zebrafish model of dopaminergic neurodegeneration.Publisher PDFPeer reviewe